Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness.
Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
Management of open angle glaucoma and ocular hypertension require long term treatment with eye drops containing preservatives. Use of preservative containing eye drops has been implicated in the development or worsening of ocular surface disease.
Symptoms and signs of ocular surface disease such as ocular surface breakdown, irritation, burning, foreign body sensation, dryness, inadequate quantity of tears, etc. are prevalent in a large proportion of patients with open angle glaucoma and ocular hypertension.
It is well known in the prior art that small organic compounds, such as benzalkonium chloride (BAC), chlorhexidine, thimerosal have excellent antimicrobial activity; however, it is now known that these small organic antimicrobials are often toxic to the sensitive tissues of the eye and can accumulate in cornea, contact lenses, particularly soft, hydrophilic contact lenses. Medications with BAC may cause disruption of the corneal surface with lower concentrations of BAC.
Gasset and Grant et al. showed that BAC accumulates in ocular tissue and remains there for long periods, adversely affecting both the corneal surface and the conjunctiva. Therefore, cessation of the medications may not immediately improve the condition and function of the ocular surface. These findings also suggest that corneal cell necrosis may occur in some patients who are taking multiple BAC-preserved ocular medications over long periods of time, even when the amount of BAC in any one medication is below the threshold concentration at which necrosis occurs.
Compared to eye drops preserved with benzalkonium chloride, preservative-free eye drops induce significantly fewer ocular symptoms and signs of irritation in patients, such as pain or discomfort, foreign body sensation, stinging or burning, and dry eye sensation.
Patients experiencing hypersensitivity reactions with benzalkonium chloride or any other kind of preservatives cannot use a commercial dorzolamide and timolol product containing benzalkonium chloride which is preserved even with 0.0075% w/v or even with as 0.005% w/v benzalkonium chloride.
Representative CAIs are disclosed in: U.S. Pat. No. 4,797,413 (Baldwin, et al.), U.S. Pat. No. 4,847,289 (Baldwin, et al.), and U.S. Pat. No. 4,731,368 (Hoffman, Jr., et al.); U.S. Pat. No. 5,153,192 (Dean, et al.), U.S. Pat. No. 5,240,923 (Dean, et al.), and U.S. Pat. No. 5,378,703 (Dean, et al.); PCT/US91/02262 (filed 9 Apr. 1990); and EP 452 151 (published 16 Oct. 1991). The entire contents of each of the above-mentioned patents and patent applications are incorporated herein by reference.
Hence, there is an unmet medical need to prepare a preservative-free ophthalmic pharmaceutical formulation wherein the preservative-free formulation induces significantly fewer ocular symptoms and signs of irritation in patients, such as pain or discomfort, foreign body sensation, stinging or burning, and dry eye sensation.
The present invention relates to the process of manufacturing pharmaceutical formulation for topical administration comprising a therapeutically effective amount of carbonic anhydrase inhibitor or ophthalmologically acceptable salts thereof and a therapeutically effective amount of hydroxyl ethyl cellulose (HEC) in combination with timolol, to be used for the treatment of ocular hypertension and glaucoma.
In the prior art various techniques were used in the pharmaceutical industry to make the high viscosity products sterile. Steam sterilization or autoclaving of ophthalmic dosage forms is common practice in pharmaceutical industry. It involves heating the ophthalmic solution or suspension, to be sterilized, placed in suitable container, at 121° C. for about 15-20 minutes. However, in many cases it is not advisable due to heat sensitivity of the drug or excipients, incompatibility of excipients with drug at higher temperature and cost involved.
In spite of that in the present formulation the inventors are using thickening agents such as HEC which is capable of building the viscosity of the solution in combination with active ingredients.
Major problems related to the ophthalmic formulations comprising HEC are that commercially HEC is available in two molecular weight range i.e. 1.0 and 1.3 million Dalton having an approximate diameter of around 0.1 and 0.13 microns respectively (assuming spherical shape) as shown in Table 1. Since the diameter of HEC is very close to the pore size of the filter, it is not possible to filter HEC through sterilizing filter, having the pore size of 0.22 microns.
TABLE 1Relationship between molecular weight andapproximate molecular diameter.Molecular weight(Dalton)Diameter (Micron)1,000,0000.11,300,0000.13
In-situ sterilization of HEC solution is possible. However, in-situ sterilization of HEC results in significant loss of viscosity as shown in Table 2. Further, even after loss of viscosity of HEC, it is not possible to pass the HEC solution through sterilization grade of filters.
TABLE 2Effect of temperature at 121° C. for various times onviscosity of HEC.Low ViscosityHigh Viscosity (HEC 250Condition(HEC 250 HX - 1.0%)HHX - 0.9%)Initial 116 cps247.5 cpsAfter 121° C./1 hrs93.3 cps255.3 cpsAfter 121° C./2 hrs57.3 cps178.6 cpsAfter 121° C./3 hrs55.7 cps  164 cpsAfter 121° C./4 hrs33.7 cps  111 cps
The inventors of the present invention surprisingly have discovered a narrow window of heating HEC solution such that minimal loss of viscosity occurs and it is possible to filter the HEC solution through aseptic filtration technique. It involves slow heating the ophthalmic solution or suspension, within a narrow window temperature range between from about 94° C. to from about 97° C. through a sterilization filter of pore size of 0.22 microns while still achieving the viscosity of 100±10 cps as shown in FIG. 1. While working on the development of the present ophthalmic solution dosage form, present inventors have embarked upon a simple technique, which eliminates the steam sterilization and/or autoclaving.
The present inventors have now developed simpler and cost effective process(s) to prepare pharmaceutical ophthalmic formulations in a single tank, without the use of additional tanks that can be sterile filtered.